RU2839752C1 - Desloratadine-based drug preparation - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: present invention relates to a desloratadine-based drug in the form of capsules having the appearance of a soft shell and a liquid content, which consists of desloratadine, polyethylene glycol, butylhydroxytoluene and carboxylic acid, with following amount of substances in mg per ml: desloratadine 1-13; butylhydroxytoluene 1-5; carboxylic acid 2-8; polyethylene glycol – balance, wherein the shell includes gelatine, liquid sorbitol or glycerol and water, and the carboxylic acid is selected from the group: ascorbic acid, adipic acid, acetic acid, tartaric acid, fumaric acid, gluconic acid, malic acid, citric acid, oxalic acid, lactic acid, formic acid, succinic acid, wherein density of capsule content does not exceed its average density, which is in range of 1.05-1.3 g/cm³.

EFFECT: present invention widens range of drugs, reduced excipients in the preparation, more uniform distribution of the active substance in the gastrointestinal tract for more uniform and complete desloratadine absorption, faster assimilation, as well as high stability of the preparation during storage.

1 cl, 3 tbl, 5 ex

Description

The invention relates to pharmaceuticals and medicine, namely to medicinal preparations based on desloratadine in the form of capsules for the treatment of allergic diseases.

Over the past decades, there has been a significant increase in the frequency and severity of allergic reactions. High prevalence of allergic diseases is observed in megacities, which is associated with an unfavorable environmental situation. Among residents of ecologically unfavorable regions, the prevalence of allergic diseases, the manifestations of which are dermatitis, bronchial asthma, hay fever, etc., is more than 50%. The most effective drugs in the treatment of allergic reactions are antihistamines, of which one of the most effective is desloratadine.

Desloratadine has antiallergic, antipruritic and antiexudative effects. Reduces capillary permeability, prevents tissue edema, relieves smooth muscle spasm. After oral administration, it begins to be determined in plasma after 30 minutes. Food does not affect distribution. Bioavailability is proportional to the dose in the range from 5 mg to 20 mg. Desloratadine can be taken regardless of food intake.

Desloratadine is the most powerful H1-histamine receptor blocker among all known antihistamines. It has a selective blocking effect, while there is no sedative effect, since desloratadine does not penetrate the blood-brain barrier, it has a stable high therapeutic effect and has a high level of safety (Lefterova M.I. "Development of the composition and technology of desloratadine tablets and syrup." Diss. for the degree of candidate of pharmaceutical sciences. Kazan, 2017).

Desloratadine is an active metabolite of loratadine, a selective second-generation H1-histamine receptor blocker. The pharmacological properties of desloratadine distinguish it from other antihistamines. Selectivity for H1 receptors is an important characteristic of pharmacodynamics, including the severity of side effects. Thus, desloratadine has 60 times greater affinity for H1 receptors than for H2 receptors. It has the highest affinity among other second-generation drugs: 200 times greater than fexofenadine, 50 times greater than loratadine and cetirizine, and 3 times greater than levocetirizine (Lefterova M.I., Kamaeva S.S., Anisimov A.N., Gubaydullin A.T., Lefterova M.I. “Study of the physicochemical and technological properties of desloratadine substances.” Modern Problems of Science and Education. 2015. No. 2-3)

Preparations containing desloratadine are available in tablets, solutions and syrups.

There are known preparations in the form of a solution for oral administration - Blogir-3, Dezal, Desloratadine VP, Desloratadine DS. As auxiliary substances they contain propylene glycol, sorbitol, hypromellose, sucralose, sodium citrate, flavorings, citric acid and water. Some preparations additionally contain disodium edetate.

Medicinal substances in solutions have the highest biological availability, are absorbed faster and have a therapeutic effect faster. However, the solution form has significant disadvantages - problems with precise dosing of liquids (especially in domestic conditions), a high probability of hydrolytic and microbiological processes, instability during storage. The main disadvantage of liquid dosage forms is instability, that is, microbial contamination in solutions is possible. Therefore, liquid dosage forms have a short shelf life after opening the package. The second negative aspect of liquid dosage forms is that substances in dissolved form are more susceptible to hydrolysis and oxidation processes than in dry form (Talykova N.M., Turetskova V.F. Medical solutions: an electronic textbook on pharmaceutical technology for full-time and part-time students of the Faculty of Pharmacy. Barnaul: Publishing house of the State Budgetary Educational Institution of Higher Professional Education "Altai State Medical University" of the Ministry of Health of the Russian Federation, 2014; I.A. Murashkina, A.A. Posokhina. "Liquid dosage forms". Textbook. In 4 parts. Part 1. Solutions: textbook. Irkutsk State Medical University, Department of Pharmacognosy and Pharmaceutical Technology. Irkutsk: Irkutsk State Medical University, 2022).

In tablet form, preparations with desloratadine are produced under the names Blogir-3, Dezal, Desloratadine-Velpharm, Desloratadine-Canon, Desloratadine-AKOS, Desloratadine-VERTEX, Delorsin, Lazamirt, Lordestin, Nalorius, Ezlor, Erius, Eslontin. As auxiliary substances, the tablets contain (in various combinations and sets) - calcium dihydrogen phosphate dihydrate, starch, microcrystalline cellulose, talc, magnesium stearate, lactose, povidone, croscarmellose, hypromellose, colloidal silicon dioxide, dye, mannitol, aspartame, citric acid monohydrate, propylene glycol, maltodextrin. The tablets are covered with a rapidly disintegrating film coating.

However, tablet forms of drugs containing tablet-specific excipients have significant drawbacks. In recent years, it has been shown that many people harm their health by taking drugs in tablet form. It has been shown that when dissolved, modern tablets can acquire high physicochemical aggressiveness similar to salts, acids and/or alkalis. In particular, it has been demonstrated that tablets of many drugs have excessively strong osmotic and acidic activity, which causes their cauterizing effect. This is why tablets can cause damage to tooth enamel and the mucous membrane of the oral cavity and stomach, which can manifest itself in caries, gingivitis, stomatitis, gastritis and stomach ulcers. The studies of tablet forms of drugs have shown that their main active and/or auxiliary components are salts. Therefore, when pressing powders, they turn the tablet into a piece of pressed salt, which, due to excessively high physicochemical activity, causes a local irritating, cauterizing and ulcerogenic effect on the digestive system. Clinical observations of the process of taking tablets orally were carried out. In the vast majority of cases, patients swallow tablets not lying down, but standing or sitting. In this regard, under the influence of gravity, the tablets fall to the bottom of the stomach in the area of its pylorus. At the same time, modern tablets of drugs aggressively affect the gastric mucosa. (Urakov A.L. "Tablet as a dosage form of drugs intended for oral administration: advantages and disadvantages." General Pharmacology. 2018, Vol. 16, No. 3. pp. 13-18. doi: 10.17816 / RCF16313-18). The results of similar studies also showed that all modern tablets are heavy, highly dense and sink quickly. After entering the stomach cavity, they fall down, sink in the liquid and sink to the very bottom, where the drug is localized in a small area. Moreover, some tablets stick to the gastric mucosa and stop moving when the stomach's location in space changes. A very important feature of the dynamics of the mechanical properties of tablets inside the stomach cavity is the stability of their location area over a fairly long period of time. It was found that almost all modern tablets (except for tablets of enveloping agents) do not disintegrate for more than 20 minutes after entering the stomach (possibly due to the above problems) and during this period of time do not form a cloud of suspension and/or emulsion around themselves. They are capable of exerting a local irritating and cauterizing effect (G.I. Ivonin, A.L. Urakov. “Mechanics of the production and intragastric destruction of food lumps and medicinal tablets.” Journal of scientific articles “Health and education in the 21st century.” 2015, Vol. 17, No. 1).

In the form of syrup, the drug desloratadine is produced under the names: Desloratadine, Lorcazid, Lordestin, Eritadine, Erius. As auxiliary substances, the syrups contain (in various combinations and sets) propylene glycol, sorbitol, citric acid, sodium citrate dihydrate, sodium cyclamate, sodium benzoate, sucrose, sucralose, hypromellose, disodium edetate, flavoring, dye, water.

The advantage of syrups is their high bioavailability compared to solid dosage forms, due to the fact that the drug is already in a dissolved state. However, syrups have significant drawbacks - instability during storage and use after opening the package. The instability of syrups is due to both physicochemical and biological nature. The former is manifested in the precipitation of sediment during storage and can lead to a change in the uniformity of dosing. The second is associated with a tendency to increase microbial contamination during the use of the syrup and is due to the fact that sweeteners are a good environment for the reproduction of microorganisms (M.E. Kim, E.F. Stepanova, S.B. Evseeva. "Syrups: composition, technology, current state of research (literature review)". Pharmacy and Pharmacology. No. 3, 2014. pp. 7-14).

To level out these shortcomings, as well as a number of others, in particular, such as possible unpleasant organoleptic properties, in liquid forms it is necessary to use a wide range of additional auxiliary substances. However, this, in turn, becomes a significant disadvantage, since additional auxiliary substances themselves can cause side effects and have contraindications. On the other hand, it is known that auxiliary substances introduced into the composition of a medicinal product can interact both with each other and directly with the active substance. As a result, such interactions may be accompanied by changes in the chemical properties, stability of the drug, pharmacokinetics, biotransformation and pharmacological activity of the drug (Bochkov P.O., Kolyvanov G.B., Litvin A.A., Zherdev V.P., Shevchenko R.V. "The Effect of High-Molecular Excipients on Optimizing the Pharmacokinetic Properties of Drugs." Pharmacokinetics and Pharmacodynamics. No. 1, 2016. Pp. 3-11). Accordingly, the fewer additional excipients in a drug that are not directly related to ensuring the bioavailability and therapeutic efficacy of the drug, the better.

Thus, ready-made liquid forms (solutions, syrups) have common disadvantages - inaccurate dosing, high probability of microbial contamination, a large set of auxiliary substances that have their own contraindications and side effects, high instability during storage due to hydrolytic and oxidative processes.

The above-mentioned disadvantages of drugs in the form of tablets or liquids are not inherent in dosage forms in the form of capsules. Capsules are a dosed dosage form consisting of a hard or soft gelatin shell containing one or more active substances with or without the addition of excipients. Capsules are divided into: hard, soft, microcapsules, gastro-resistant, pellets. Gastro-resistant - capsules that provide the release of drugs in intestinal juice. Microcapsules - capsules consisting of a thin shell made of a polymer or other material, spherical or irregular in shape, from 1 to 2000 μm in size, containing solid or liquid active substances with or without the addition of excipients. Soft - whole capsules of various shapes (spherical, ovoid, oblong, etc.) with liquid or pasty substances. Hard - cylindrical capsules with hemispherical ends, consisting of two parts that fit one into the other without forming gaps. Capsules can be filled with powders, granules, microcapsules, pellets, tablets. Pellets - coated solid particles of spherical shape containing one or more active active substances with or without the addition of excipients, having dimensions from 2000 to 5000 µm (Industry standard 91500.05.001-00 "Quality standards for medicines").

Advantages of capsules: high bioavailability; release of the active substance in the desired section of the gastrointestinal tract (GIT); dosing accuracy; high stability; masking of unpleasant odor and taste; reduced likelihood of hydrolytic and oxidative processes in the capsule contents; reduced irritating effect of the drug; long shelf life.

To obtain capsules, a wide range of substances is used - film formers, allowing to obtain elastic films with a certain mechanical strength: gelatin, casein, agar-agar, simple and complex cellulose ethers, copolymer of methacrylamide and methacrylic acid, etc. The most common material is gelatin (a product of partial hydrolysis of collagen). In addition to hydrogels and analogues, the main substances of the capsule include plasticizers - substances that impart the necessary elasticity to the capsule shells, mainly glycerin, sorbitol, polyethylene glycols and other substances or their compositions. They may also include preservatives (nipagin, nipazole, sorbic acid, mixtures of benzoic acid and sodium benzoate, etc.), dyes (carminic acid, chlorophyll, b-carotene, titanium dioxide, yellow, red and black iron oxide, eosin, erythrosine, indigo, acid red 2C, etc.), opacifiers (substances that make it possible to obtain opaque capsules due to the ability to form a stable fine suspension in the gelatin mass), water-absorbing agents (substances that prevent the possibility of water passing from the capsule shell to hygroscopic substances that may be part of the capsule contents), disintegrants (ingredients that prevent the destruction of capsule shells during long-term storage or promote the rapid release of contents from the capsule - amino acids, proteins, casein, tween, sodium bicarbonate, etc.), agents that prevent possible sticking of capsules - D-mannitol, D-sorbitol, xylitol (https://portal.tpu.ru/SHARED/t/TRUSOVA/learn/Technology%20GLS_2012_2017/Tab1/Л%208%20Каспулы.pdf).

The composition of the ingredients and the shape of the capsule shell should be combined with the characteristics of the capsule contents, which, in turn, should include suitable excipients that ensure bioavailability and maintain or improve the specific activity of the active substance. As is known, the solubility of the main component of a drug has an ambiguous effect on the properties of the manufactured dosage form (DF). Thus, researchers, on the one hand, are faced with the need to increase solubility in order to increase the bioavailability of the drug, and at the same time control the dissolution profile in order to level out sharp jumps in drug concentrations in the systemic bloodstream, as well as increase the residence time of the drug (DS) in the body. The presence of high-molecular excipients in the DF is one of the main factors affecting the degree and rate of absorption of drugs from the gastrointestinal tract into the systemic bloodstream. It is known that excipients (ES) introduced into the DF can interact both with each other and directly with the DS. As a result, such interactions are accompanied by changes in the chemical properties, stability of the dosage form, pharmacokinetics, biotransformation and pharmacological activity of the drug. The interaction between the components of the dosage form can be both chemical bonds and electrostatic attraction due to polarity and the formation of hydrogen bridges. Thus, the mixed nature of the interaction between atoms, molecules and ions of the components of the dosage form determines its new physicochemical properties. This is reflected in changes in solubility, diffusion coefficient, lipid-water distribution coefficient and, as a consequence, in changes in the penetrating ability of the active substance through biological membranes. In other words, the introduction of solubilizers into the composition of the dosage form changes the bioavailability (BA) of the drug compound. Additionally, the use of solubilizers can be used to reduce the dosage of the drug due to faster and more complete absorption of the drug (Bochkov P.O., Kolyvanov G.B., Litvin A.A., Zherdev V.P., Shevchenko R.V. “The influence of high-molecular excipients on the optimization of the pharmacokinetic properties of drugs.” Pharmacokinetics and pharmacodynamics. No. 1, 2016. Pp. 3-11).

Thus, given the wide variety of compounds for obtaining capsule shells and their contents, to create a medicinal product based on desloratadine in the form of capsules, it is necessary to conduct numerous experiments and studies to study the interaction of suitable substances, their quantitative combination, providing the required characteristics of the medicinal product, both from the standpoint of high bioactivity and bioavailability, and from the standpoint of acceptable organoleptic characteristics, shelf life and physical and mechanical properties.

On the other hand, it is known that the prescription and oral administration of solid dosage forms is currently carried out without controlled and managed movement of them inside the stomach, which reduces the effectiveness and safety of enteral administration of drugs, especially in diseases of the stomach (Korovyakov A.P., Vakhrushev Ya.M., Strelkov N.S., Urakov A.L., Urakova N.A., Urakova T.V., Korepanova M.V., Muravtseva T.M., Feigin E.V. "Individual Features of Controlling the Process of Physical Movement of Solid and Liquid Dosage Forms Inside the Stomach." Experimental and Clinical Gastroenterology. 2003, No. 1. pp. 3-32). Moreover, the stomach cavity allows for simple and reliable movement of drugs inside it “in the right direction”, since the movement of drugs inside various cavities of the body, including the stomach cavity, depends not only on the peristalsis of their walls, but also on the discrepancy between the specific gravity of drugs and liquids located in these cavities (Strelkov N.S., Urakov A.L., Korovyakov A.P., Muravtseva T.M., Korepanova M.V., Urakova N.A., Feigin V.P. “Clinical Features of Passive Intragastric Pharmacokinetics of Astringent, Enveloping, Adsorbing and Antacid Medicines”. Morphological Gazette. 2002, No. 3).

In other words, in addition to biochemical characteristics, the developed capsules with desloratadine must meet certain physical and mechanical requirements, such as the average density of whole capsules and their contents in order to ensure a more complete and uniform release of the active substance from the capsule and its uniform distribution in the gastrointestinal tract.

In this case, it is necessary to take into account the physicochemical properties of the active substance. Desloratadine, in the presence of many fillers, including lactose, forms the decomposition product of desloratadine 1-formyl. Desloratadine is a light-sensitive drug (Lefterova M.I., Kamaeva S.S., Anisimov A.N. "Development of the composition and technology of desloratadine tablets using a full factorial experiment." FUNDAMENTAL RESEARCH. No. 2, 2015. Pp. 2631-2636). Desloratadine is committed to polymorphism. The existence of several polymorphic modifications of desloratadine is known. In the US patent application (US20060223841) the physical properties of polymorphic forms I and II were compared with the properties of their physical mixtures (25:75, 50:50, 75:25, 84:16 polymorphic forms I and II). It was found that polymorphic mixtures with different compositions have unchanged physical properties compared to individual polymorphic forms I and II. Water is also present in the desloratadine substance produced by various companies. It is known that the presence of water in the substance plays a significant role in the manufacture and storage of the finished dosage form - with a higher water content, the amount of foreign impurities increases. However, it should be borne in mind that the water present in the substance is adsorption, not crystallization, i.e. is not part of the crystalline packing of the compounds, but accumulates at the boundaries of crystallites (Lefterova M.I., Kamaeva S.S., Anisimov A.N., Gubaydullin A.T., Lefterova M.I. “Study of the physicochemical and technological properties of desloratadine substances”. Modern problems of science and education. 2015, No. 2, part 3). At the same time, the ability of mutual transition of crystalline and amorphous forms during production and storage under the influence of various physicochemical factors is known, which requires a thorough study of the aspects of crystallographic instability and taking measures to ensure conditions that exclude undesirable changes in the crystalline structure of the substance. For example, the phenomenon of conversion of a more soluble crystalline form into a less soluble form is known during the production of a liquid suspension form, accompanied by the formation of a non-resuspendable sediment in the finished form. Crystallographic changes in the primary form of the active substance can occur at different stages and under different conditions of technological processing. Differences in the solubility of polymorphic forms can have a significant impact on bioavailability and, accordingly, therapeutic efficacy. Various polymorphic forms can differ in melting point, hygroscopicity, physical and chemical stability, solubility, bioavailability, and technological parameters. At the same time, metastable forms, as a rule, are characterized by a higher dissolution rate compared to the stable crystalline polymorphic form. Differences in the solubility of polymorphic forms can have a significant impact on bioavailability and, accordingly, therapeutic efficacy. As is known, to obtain the required pharmacotherapeutic effect, the active substance must be at the site of its action for the required amount of time. The concentration of drugs in the systemic bloodstream depends on a number of factors, including the degree of absorption, the characteristics of distribution between the systemic bloodstream and other tissues and body fluids, metabolism and elimination parameters. Thus, factors influencing the absorption processes determine the amount of a drug entering the body and, accordingly, have a direct impact on bioavailability and the pharmacotherapeutic effect. If we consider the situation with the same dosing regimen (dose, frequency and time of administration), the following factors may be significant in terms of their impact on the absorption process: factors associated with the biopharmaceutical parameters of the finished dosage form (physicochemical properties of the active substance, type of finished dosage form and its characteristics, composition and characteristics of excipients, technological parameters of the production process); external factors not associated with the patient and the drug, but modifying the absorption process (food intake, concomitantly taken drugs). The key biopharmaceutical properties determined by biopharmaceutical factors and influencing the absorption of solid dosage forms (tablets, capsules) are: - release of the pharmacologically active substance from the dosage form into the solution (solubility and dissolution kinetics); stability of the dissolved substance in physiological fluids; transport of the drug through biological membranes (permeability); susceptibility to presystemic metabolism. In general, the dosage form is formed in order to ensure and control the required release and dissolution of the active substance. The dissolved substance is subject to absorption, in this regard, the dissolution process (the amount and rate of transition of the drug into solution) is one of the most significant factors in ensuring the required bioavailability of the pharmacologically active substance from the finished dosage form. Significant physiological factors are pH, buffer capacity, surfactant content in gastric juice and bile, the presence of food components and viscosity of cavity contents, gastrointestinal motility, gastrointestinal secretion and the amount of fluid in the drug dissolution zone. Each of these factors has a different effect on the parameters of the drug dissolution rate. Associations of drug molecules and solvent molecules can be considered as another crystallographic form (sometimes referred to as a pseudopolymorphic form), which also modifies the dissolution property of the drug. In general, solvation of the crystal reduces solubility and dissolution rate, thus affecting bioavailability, in particular, of poorly soluble drugs, which significantly depends on the dissolution rate (Setkina S.B., Khishova O.M. “Biopharmaceutical aspects of drug technology and ways of modifying bioavailability”. VESTNIK VSMU, 2014, Vol. 13, No. 4. Pp. 162-172).

Taking into account the above factors and prerequisites, the objective of the present invention is to obtain a new dosage form based on desloratadine, possessing the required biochemical and physicomechanical properties while minimizing the disadvantages inherent in known tablet and liquid forms.

The technical result of the invention is the expansion of the arsenal of medicinal products, the reduction of auxiliary substances in the preparation, the increase in the uniformity of the distribution of the active substance in the gastrointestinal tract to increase the uniformity and completeness of the absorption of desloratadine, the acceleration of its assimilation, and the provision of high stability of the preparation during storage.

The technical result is achieved by the fact that the drug is in the form of soft capsules, the contents of which consist of desloratadine, polyethyleneglycol, butylhydroxytoluene and carboxylic acid, with the following amount of substances in mg per ml:

Desloratadine 1 - 13 Butylated hydroxytoluene 1 - 5 Carboxylic acid 2 - 8 Polyethylene glycol rest,

and the shell includes gelatin, liquid sorbitol or glycerin and water, wherein the carboxylic acid is selected from the group: ascorbic, adipic, acetic, tartaric, fumaric, gluconic, malic, citric, oxalic, lactic, formic, succinic. In this case, the density of the capsule contents does not exceed its average density, which is within the range of 1.05 - 1.3 g / cm ³ . Additionally, the shell may contain titanium dioxide and other dyes.

This set of essential features is unknown from the state of the art, meets the criteria of inventive step and industrial applicability. The composition was obtained as a result of studies and experiments, since it is impossible to predict in advance the behavior of a new combination of different organic compounds and the effects exhibited both at the stage of the drug production technology and during storage. This is especially true for a combination of polyethylene glycol and a representative of phenols (ionol), in which, under certain conditions, non-covalent binding of phenols by polymers may occur, in particular, such as polyethylene glycol (E.V. Anufrieva, M.G. Krakovyak, R.A. Gromova, V.B. Lushchik, T.D. Ananyeva, T.V. Sheveleva. "Collapse of Macromolecules of Water-Soluble Polymers under the Action of Phenol". High-Molecular Compounds. Series A. 1998, Vol. 40, No. 11. Pp. 1870-1875).

Taking into account the physical properties and quantitative ratio of the ingredients of the preparation, the corresponding density of the capsules was obtained for the optimal speed of immersion and their simultaneous dissolution in the stomach. At the same time, the difference in the average density of the capsule and its contents ensures a more uniform distribution of the contents in the volume of the stomach during the disintegration of the capsule, both in the presence of food and without it.

The invention is illustrated by the examples presented below.

Example 1

The capsules are obtained as follows.

The calculated amount of polyethyleneglycol (macrogol-600) is loaded into the reactor with the mixer turned on. The reactor with macrogol-600 is heated to a temperature of 70 ^° C. Then the prepared amount of butylhydroxytoluene is loaded into the reactor with heated polyethyleneglycol with constant stirring. Then, while continuing to stir, the mass is cooled to a temperature of 50 ^° C, after which the specified amount of desloratadine is loaded into the reactor with stirring. Upon reaching complete dissolution of desloratadine, the mass is cooled to a temperature of 30 ^° C with continuing stirring. Then carboxylic acid is loaded into the reactor. Stirring is continued until complete homogeneity of the mixture is achieved. The resulting product is filtered.

The capsule shell material is obtained as follows. The prepared amount of purified water for the suspension is loaded into the process container, then the required amount of dye - titanium dioxide is loaded with constant stirring. The suspension is stirred for 45 minutes until completely homogeneous. The prepared amount of purified water for the preparation of the gelatin mass is loaded into a separate reactor. The water is heated to a temperature of 75 ^° C and the prepared amount of dye and plasticizer, which is liquid sorbitol, are added to the water. The mixture is stirred, and then gelatin is added to it in portions. After loading the first portion of gelatin, the mass is maintained with stirring and a temperature of 75 ^° C for 20 minutes. Then the vacuum is turned on and the mass is maintained with stirring for about 30 minutes. After this, the vacuum is released and the previously obtained titanium dioxide suspension is loaded with stirring. The mass is stirred. Then the second portion of gelatin is loaded and mixed at a temperature of 75 ^° C for 10 minutes. The vacuum is turned on and the mass is mixed for 120 minutes. The vacuum is released. After the deaeration time has elapsed and there are no air bubbles in the gelatin mass, the temperature in the reactor is reduced to 60 ^° C and the mass is left in the reactor for stabilization for at least 120 minutes.

Upon completion of preparation, the gelatin mass should have a temperature of 60 ^° C and a viscosity of 8,000 - 12,000 cP*s. A gelatin ribbon is formed from the resulting gelatin mass, which is sent to an encapsulating machine to obtain capsules with liquid contents. The resulting capsules are dried until the capsules reach a specified average weight of 440 mg. The finished soft gelatin capsules have an oval shape. The contents of the capsules are a transparent liquid from colorless to red.

Example 2

The shell contains glycerin as a plasticizer.

Example 3

The study of dissolution kinetics (transition of the active substance, desloratadine, into the model solution in percent) was carried out for the capsules of the preparation obtained according to example 1. The quantitative determination of desloratadine transferred into the dissolution medium was carried out on a spectrophotometer. The dissolution medium is a phosphate buffer solution, pH 6.8.

Example 4

The dissolution kinetics study was carried out for the capsules of the drug obtained according to Example 2, similarly to Example 3. The dissolution medium was a 0.1 M hydrochloric acid solution.

Example 5

The dissolution kinetics study was carried out for the capsules of the drug obtained according to Example 2 similarly to Example 3. The dissolution medium was an acetate buffer solution with a pH of 4.5.

As can be seen from the examples, the capsules obtained according to the present invention disintegrate in model solutions simulating the gastric environment with varying degrees of acidity within 10-15 minutes, during which the active substance almost completely passes into the gastrointestinal tract. Moreover, the transition occurs gradually, ensuring uniform distribution of desloratadine due to the movement of the disintegrating capsule along the gastrointestinal tract during this period of time. This, in turn, leads to uniform absorption of the active substance. The drug demonstrated high stability during storage for 2.5 years. Deviations in the indicators for this period compared to freshly prepared capsules did not exceed 4% on average.

Claims (3)

A medicinal product based on desloratadine in the form of capsules that have the appearance of a soft shell and liquid contents, which consists of desloratadine, polyethyleneglycol, butylhydroxytoluene and carboxylic acid in the following amount of substances in mg per ml: desloratadine 1-13 butylated hydroxytoluene 1-5 carboxylic acid 2-8 polyethylene glycol rest wherein the shell comprises gelatin, liquid sorbitol or glycerin and water, and the carboxylic acid is selected from the group: ascorbic, adipic, acetic, tartaric, fumaric, gluconic, malic, citric, oxalic, lactic, formic, succinic, while the density of the capsule contents does not exceed its average density, which is within the range of 1.05-1.3 g/ ^cm3 .